Despite intensive pharmacological and psychosocial interventions, many schizophrenic patients remain relatively unresponsive to treatment. Few such enter university-based intensive neuroscience research studies. We propose to investigate the biological basis of treatment-resistance in schizophrenia by using PET and EEG methodologies. We will further develop existing university-state hospital collaboration by establishing an EEG facility at Metropolitan State Hospital and provide training for additional research staff through a new sabbatical staff training program. Our research strategy is based on two observations in patients with schizophrenia: (1) a relatively altered basal ganglia metabolic rate when measured by PET imaging with 18-F 2-deoxyglucose (FDG); and (2) a relatively decreased spectral energy in the EEG alpha range. In studies of groups of schizophrenic patients who show clinical response, brain FDG metabolic activity on PET and cortical EEG alpha activity are significantly changed by neuroleptic drugs, primarily in the direction toward normalization. We propose to contrast drug-free baseline and on-neuroleptic EEG and PET measurements in 54 schizophrenic patients divided on the basis of clinical response to a prospective trial with haloperidol and clozapine into three groups: a haloperidol-responsive group, a haloperidol-nonresponsive but clozapineresponsive group, and a treatment-resistant group who fail to respond to both drugs. Multivariate analyses contrasting these three groups on measures of glucose metabolism with PET in specific brain areas (basal ganglia) and an alpha EEG spectral power will be conducted to evaluate whether the three groups can be biologically distinguished at baseline, and whether a differential effect of treatment with the typical neuroleptic haloperidol and the atypical neuroleptic clozapine is observed in the three groups in repeated PET and EEG assessment.